Unwanted tissue reactions are often observed resulting in events such as early resorption of the biomaterial, loosening of the implant, or a chronic (immunologic) response. From immunologic studies it is known that inflammatory reactions can be modulated by use of (anti)-growth factors or anti-inflammatory drugs. Before this can be employed with respect to biomaterials, the role of individual factors (humoral and cellular) has to be studied. In this part of the investigation, the role of T cells was studied by use of T-cell-deficient (nude) rats and control (AO) rats. Hexamethylenediisocyanate-crosslinked dermal sheep collagen (HDSC) was selected as the test material. The results showed that T cells or T cell-related factors played a prominent role in the attraction of macrophages and the formation of giant cells, their antigen presentation, and their phagocytotic capacity. As a consequence, degradation of HDSC was strongly delayed. This study also showed that infiltration of fibroblasts and creation of stromal areas in HDSC was restricted to areas subjected to degradation. However, in time, absence of T cells resulted in increased formation and maturation of autologous rat collagen. Results obtained suggest that the inflammatory reaction to biomaterials might be modulated by controlling T-cell activation.